Increase of Opioid μ-Receptor Gene Expression in Streptozotocin-Induced Diabetic Rats

Opioids play an important role in the regulation of glucose homeostasis. In the previous report, we showed that activation of opioid µ-receptors produced a plasma glucose lowering effect in diabetic rats lacking insulin. In the present study, we found that the response of opioid µ-receptor is more sensitive in streptozotocin-induced diabetic rats (STZ-diabetic rats) than in normal rats. Intravenous injection of loperamide, an agonist of opioid µ-receptors, induced a dose-dependent decrease of plasma glucose from 3 μg/kg to 60 μg/kg in fasting STZ-diabetic rats. However, loperamide decreased the plasma glucose of normal fasting rats at the doses of 0.3 mg/kg to 1.5 mg/kg, which were much higher than those needed to produce the same effect in diabetic rats. The plasma glucose-lowering action of loperamide at the dose effective in normal rats disappeared in opioid µ-receptor knockout mice, while the plasma glucose-lowering response to loperamide was still observed in wild-type mice. This opens the possibility of mediation through opioid µ-receptor in the plasma glucose-lowering action of loperamide. Moreover, the mRNA level of opioid µ-receptor in the liver markedly increased in STZ-diabetic rats compared to normal rats. Normalization of plasma glucose concentrations in STZ-diabetic rats with exogenous insulin or phlorizin reversed mRNA and protein levels of opioid µ-receptor in the liver after 4 days of treatment. This shows that correction of hyperglycemia in STZ-diabetic rats may reverse the higher gene expression of opioid µ-receptor. These results suggest that hyperglycemia is responsible for increase of opioid µ-receptor in STZ-diabetic rats.

Diabetic Rats - Insulin-Opioid µ-Receptor - Phlorizin

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